Antioxidant system disturbances and mitochondrial dysfunction induced by 3-methyglutaric acid in rat heart are prevented by bezafibrate.

Barth syndrome (BTHS) and dilated cardiomyopathy with ataxia syndrome (DCMA) are biochemically characterized by high levels of 3-methylglutaric acid (MGA) in the urine and plasma of affected patients. Although cardiolipin abnormalities have been observed in these disorders, their pathophysiology is not fully established. We evaluated the effects of MGA administration on redox homeostasis and mitochondrial function in heart, as well as on vascular reactivity in aorta of Wistar rats without cardiolipin genetic deficiency. Potential cardioprotective effects of a pretreatment with bezafibrate (BEZ), a pan-PPAR agonist that induces mitochondrial biogenesis, were also determined. Our findings showed that MGA induced lipid peroxidation, altered enzymatic and non-enzymatic antioxidant defenses and reduced respiratory chain function in rat heart. MGA also increased Drp1 and reduced MFN1 levels, suggesting mitochondrial fission induction. Moreover, MGA altered MAPK and Akt signaling pathways, and had a strong tendency to reduce Sirt1 and PGC-1α, indicative of mitochondrial biogenesis impairment. Aorta vascular reactivity was further altered by MGA. Additionally, BEZ mitigated most alterations on antioxidant defenses and mitochondrial quality control proteins provoked by MGA. However, vascular reactivity disturbances were not prevented. It may be presumed that oxidative stress, mitochondrial bioenergetics and control quality disturbances, and vascular reactivity impairment caused by MGA may be involved in the cardiac failure observed in BTHS and DCMA, and that BEZ should be considered as a pharmacological candidate for the treatment of these disorders.

Ethylmalonic acid impairs bioenergetics by disturbing succinate and glutamate oxidation and induces mitochondrial permeability transition pore opening in rat cerebellum.

Tissue accumulation and high urinary excretion of ethylmalonic acid (EMA) are found in ethylmalonic encephalopathy (EE), an inherited disorder associated with cerebral and cerebellar atrophy whose pathogenesis is poorly established. The in vitro and in vivo effects of EMA on bioenergetics and redox homeostasis were investigated in rat cerebellum. For the in vitro studies, cerebellum preparations were exposed to EMA, whereas intracerebellar injection of EMA was used for the in vivo evaluation. EMA reduced state 3 and uncoupled respiration in vitro in succinate-, glutamate-, and malate-supported mitochondria, whereas decreased state 4 respiration was observed using glutamate and malate. Furthermore, mitochondria permeabilization and succinate supplementation diminished the decrease in state 3 with succinate. EMA also inhibited the activity of KGDH, an enzyme necessary for glutamate oxidation, in a mixed manner and augmented mitochondrial efflux of α-ketoglutarate. ATP levels were markedly reduced by EMA, reflecting a severe bioenergetic disruption. Docking simulations also indicated interactions between EMA and KGDH and a competition with glutamate and succinate for their mitochondrial transporters. In vitro findings also showed that EMA decreased mitochondrial membrane potential and Ca2+ retention capacity, and induced swelling in the presence of Ca2+ , which were prevented by cyclosporine A and ADP and ruthenium red, indicating mitochondrial permeability transition (MPT). Moreover, EMA, at high concentrations, mildly increased ROS levels and altered antioxidant defenses in vitro and in vivo. Our data indicate that EMA-induced impairment of glutamate and succinate oxidation and MPT may contribute to the pathogenesis of the cerebellum abnormalities in EE.

Immunotherapy using PD-1/PDL-1 inhibitors in metastatic triple-negative breast cancer: A systematic review.

Breast cancer is the most commonly diagnosed cancer in women and is one of the leading causes of death from cancer in women worldwide. Despite the significant benefits of using conventional chemotherapy in the treatment of breast cancer, one of its subtypes, the triple-negative breast cancer, is still a challenge in clinical practice. Recent studies have been investigating the role of the immune system in breast cancer and the development of immunotherapy. Although recently the use of atezolizumab, an anti-PD-L1 monoclonal antibody, combined with chemotherapy was approved, an important step in the treatment of patients with triple-negative metastatic breast cancer, the use of immunotherapy to treat breast tumors remains a major challenge. In this systematic literature review, following PRISMA guidelines, we searched for clinical trials using immunotherapy in the treatment of metastatic triple-negative breast cancer published until March 2020 in the databases EMBASE, PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), with no language restrictions. We did not contact the authors of the clinical trials to obtain additional information. Two researchers independently collected the data and assessed the quality of this study. The literature shows that immunotherapy with anti-PD-1/PD-L1 agents is emerging as a new treatment option in breast cancer. On the other hand, when compared to other types of cancer in which several agents have already been approved, the research is still in its infancy. The use of anti-PD-1/PD-L1 agents as monotherapy revealed encouraging results in the metastatic setting, especially when administered in the early course of the disease, although combination strategies with chemotherapy appear to increase its efficacy. The main limitation of this study is the approach of cancer only in advanced stages.

O Estado da Arte da Imunoterapia no Tratamento do Câncer de Mama Triplo-Negativo: Principais Drogas, Associações, Mecanismos de Ação e Perspectivas Futuras / The State-of-the-Art of Immunotherapy in the Triple-Negative Breast Cancer Treatment: Main Drugs, Combinations, Mechanisms of Action and Future Perspectives / El Estado del Arte de la Inmunoterapia en el Tratamiento del Cáncer de Mama Triple Negativo: Principales Fármacos, Asociaciones, Mecanismos de Acción y Perspectivas de Futuro

Introdução: O câncer de mama é o mais comumente diagnosticado em mulheres e uma das principais causas de morte por câncer em mulheres em todo o mundo. Apesar, ou talvez por causa, de sua natureza agressiva e da falta de tratamentos direcionados atuais, pesquisas clínicas e laboratoriais significativas estão fornecendo opções de tratamento diferenciadas. Historicamente, a quimioterapia tem sido a única opção viável de tratamento sistêmico para doenças precoces e avançadas. No entanto, ensaios clínicos publicados recentemente mostraram que a imunoterapia tem um papel importante no paradigma de tratamento dessa condição devastadora. Objetivo: Demonstrar o estado da arte da imunoterapia no tratamento do câncer de mama triplo-negativo. Método: Revisão integrativa de literatura, entre janeiro/2020 a março/2020, a partir das bases de dados PubMed, SciELO, InternationalClinical Trials Registry Platform e LILACS, por meio dos descritores "Imunoterapia", "Neoplasias da mama" e "Neoplasias de mama triplo negativas" e seus respectivos correspondentes em inglês. Resultados: Foram encontrados 465 artigos; destes, 457 foram excluídos após aplicação dos critérios metodológicos. Assim, restaram oito artigos que atendiam aos critérios de inclusão, demonstrando os principais agentes terapêuticos utilizados, mecanismos de ação e combinações terapêuticas. Encontraram-se 25 ensaios clínicos em andamento na plataforma de registro de ensaios clínicos InternationalClinical Trials Registry Platform. Conclusão: Embora a imunoterapia seja algo recente, seus resultados com agentes inibidores da PARP, PD-1 e PD-L1 demonstraram resultados satisfatórios. Novos ensaios com subgrupos estratificados de acordo com biomarcadores tumorais específicos são necessários, a fim de avaliar se algum subgrupo tem maior benefício ao tratamento.

Introduction: Breast cancer is the most commonly diagnosed cancer in women and is one of the leading causes of death from cancer in women worldwide. Despite, or perhaps because of its aggressive nature and current lack of targeted treatments, significant basic research and clinical trials are being conducted to provide new treatment options. Historically, chemotherapy has been the only viable systemic treatment option for early and advanced diseases. However, recently published clinical trials have shown that immunotherapy plays an important role in the treatment paradigm of this devastating clinical condition. Objective: To demonstrate the state-of-the-art results of immunotherapy in the treatment of triple-negative breast cancer. Method:An integrative literature review was carried out between January/2020 and March/2020, in PubMed, SciELO, International Clinical Trials Registry Platform and LILACS databases, using the keywords "Immunotherapy", "Breast Cancer", and "Triple Negative Breast Cancer" and its respective correspondents in Portuguese. Results: 465 articles were found; of those, 457 were excluded after applying the methodological criteria. Thus, 8 articles that met the inclusion criteria, showing the main therapeutic agents used, mechanisms of action and therapeutic combinations, remained. 25 clinical trials were found in progress on the International Clinical Trials Registry Platform. Conclusion: Although immunotherapy is somewhat recent, its results with PARP, PD-1 and PD-L1 inhibitors have shown satisfactory results. New trials with subgroups stratified according to specific tumor biomarkers are needed in order to assess if some subgroups have greater benefit to treatment.

Introducción: El cáncer de mama es el más comúnmente diagnosticado en las mujeres y es una de las principales causas de muerte por cáncer en mujeres de todo el mundo. A pesar de, o quizás debido a su naturaleza agresiva y la falta de tratamientos dirigidos actuales, investigaciones clínicas y de laboratorio significativas están proporcionando opciones de tratamiento diferenciadas. Históricamente, la quimioterapia ha sido la única opción viable para el tratamiento sistémico de enfermedades tempranas y avanzadas. Sin embargo, los ensayos clínicos publicados recientemente han demostrado que la inmunoterapia desempeña un papel importante en el paradigma del tratamiento de esta condición devastadora. Objetivo: Demostrar el estado del arte de la inmunoterapia en el cáncer de mama triple negativo. Método: Revisión integradora entre enero/2020 y marzo/2020, utilizando las bases de datos PubMed, SciELO, InternationalClinical Trials Registry Platform y LILACS, empleando las palabras clave "Inmunoterapia", "Cáncer de mama" y "Cáncer de mama triple negativo" y los respectivos términos en inglés. Resultados: Se encontraron 465 artículos; de estos, 457 fueron excluidos después de aplicar los criterios metodológicos. Así, quedaron 8 artículos que cumplían los criterios, que mostraban los principales agentes terapéuticos utilizados, mecanismos de acción y combinaciones terapéuticas. Se encontraron 25 ensayos clínicos en progreso en la plataforma InternationalClinical Trials Registry Platform. Conclusión: Aunque la inmunoterapia es algo reciente, sus resultados con inhibidores de PARP, PD-1 y PD-L1 han mostrado resultados satisfactorios. Se necesitan nuevos ensayos con subgrupos estratificados según biomarcadores tumorales específicos para evaluar si algún subgrupo tiene un mayor beneficio.

Diagnosis and treatment of müllerian malformations.

Anomalies in the müllerian ducts are congenital alterations with more prevalence than it is imagined, varying from 0.5 to 6.7% in the general population and up to 16.7% in women with recurrent miscarriage. The main findings are primary amenorrhea, dysmenorrhea, pelvic pain, endometriosis, sexual difficulties and low self-esteem. The major impact on the quality of life in women stricken by these problems justifies this study, whose objective is to analyze their most important aspects such as etiopathogeny, classification, diagnostic methods and proposed treatments. The research was performed on the Medline-PubMed database from 1904 to 2018. The American Fertility Society, European Society of Human Reproduction and Embryology, and the European Society of Gynaecological Endoscopy classify malformations as: Class 1/U5bC4V4: agenesis or hypoplasia of uterus and vagina; Class 1/U5aC4V4: cervical hypoplasia, associated with total or partial vaginal agenesis; Class 2/U4: unicornuate uterus; Class 3/U3bC2V1 or Class3/U3bC2V2: uterus didelphys; Class 4/U3C0: bicornuate uterus; Class 5/U2: septate uterus; Class 6: arcuate uterus; Class 7/U1: induced by diethylstilbestrol, represented by a T-shaped uterus; and V3: transverse vaginal septum. The diagnostic methods are the two-dimensional or three-dimensional ultrasound, MRI, hysterosalpingo-contrast-sonography, X-ray hysterosalpingography, hysteroscopy and laparoscopy. Some müllerian malformations are healed with surgery and/or self-dilatation. For vaginal agenesis, dilatation by Frank technique shows good results while malformations with obstruction of the menstrual flow need to be rapidly treated by surgery.

Bezafibrate Prevents Glycine-Induced Increase of Antioxidant Enzyme Activities in Rat Striatum.

Non-ketotic hyperglycinemia (NKH) is a severe neurological disorder caused by defects in glycine (GLY) catabolism and characterized by a high cerebrospinal fluid/plasma GLY ratio. Treatment is often ineffective and limited to the control of symptoms and detoxification of GLY. In the present work, we investigated the in vivo effects of GLY intracerebroventricular administration on oxidative stress parameters in rat striatum, cerebral cortex, and hippocampus. In vitro effects of GLY were also evaluated in striatum. The effects of bezafibrate (BEZ), a potential neuroprotective agent, on the possible alterations caused by GLY administration were further evaluated. Our in vivo results showed that GLY increased the activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) in striatum. Furthermore, GLY decreased the concentrations of total glutathione and reduced glutathione (GSH), as well as GSH/oxidized glutathione ratio in vivo in hippocampus. In vitro data also showed that GLY induced lipid peroxidation and decreased GSH in striatum. Regarding the effects of BEZ, we found that GLY-induced increase of GPx, SOD, and GR activities was attenuated or prevented by this compound. However, BEZ did not alter GLY-induced decrease of GSH in hippocampus. We hypothesize that GLY-induced increase of the activities of antioxidant enzymes in striatum occurs as a mechanism to avoid accumulation of reactive oxygen species and consequent oxidative damage. Furthermore, since BEZ prevented GLY-induced alterations, it might be considered as an adjuvant therapy for NKH.

Evidence that thiol group modification and reactive oxygen species are involved in hydrogen sulfide-induced mitochondrial permeability transition pore opening in rat cerebellum.

We report here the effects of hydrogen sulfide (sulfide), that accumulates in ETHE1 deficiency, in rat cerebellum. Sulfide impaired electron transfer and oxidative phosphorylation. Sulfide also induced mitochondrial swelling, and decreased ΔΨm and calcium retention capacity in cerebellum mitochondria, which were prevented by cyclosporine A (CsA) plus ADP, and ruthenium red, suggesting mitochondrial permeability transition (mPT) induction. Melatonin (MEL) and N-ethylmaleimide also prevented sulfide-induced alterations. Prevention of sulfide-induced decrease of ΔΨm and viability by CsA and MEL was further verified in cerebellum neurons. The data suggest that sulfide induces mPT pore opening via thiol modification and ROS generation.

Clínica e depressão / Clinic and depression / Clínica y depresión

A partir dos pontos de vista histórico e psicanalítico, este artigo visa demonstrar como é possível se perceber relações entre: 1) o afastamento da psiquiatria da tradição psicanalítica e sua aproximação de uma prática organicista-farmacológica; e 2) a transformação da depressão em grande mal do homem contemporâneo. Este artigo propõe também que investigar a constituição narcísica do homem contemporâneo pode nos ajudar a compreender como a depressão se torna um problema central no capitalismo flexível que marca a contemporaneidade.(AU)

This article’s intention is to demonstrate, from the historical and psychoanalytic points of view, how it is possible to perceive relations between: 1) the withdraw of psychiatry from psychoanalytic tradition and its approach to an organicist-pharmacological practice, and 2) the transformation of depression in the great disease of contemporary man. This article also suggests that investigating the constitution of the narcissism of contemporary man can help us to understand how depression became a central issue in a reality dominated by the flexible capitalism.(AU)

Este artículo comprende, desde los puntos de vista histórico y psicoanalítico, que es posible percibir relaciones entre: 1) una separación de la psiquiatría de la tradición psicoanalítica y su enfoque en una práctica organicista-farmacológica, y 2) la transformación de la depresión en el grande mal del hombre contemporáneo. Este artículo también propone que investigar la constitución del narcisismo del hombre de nuestro tiempo nos posibilita interpretar que la depresión se ha vuelto un problema central del mundo contemporáneo, dominado por el capitalismo flexible.(AU)

Improvement of the lipid profile in post menopausal women who use estradiol and testosterone implants.

OBJECTIVE: This study evaluating the lipid profile in women in post menopause using the hormone therapy (HT) with implants of estradiol and testosterone. METHOD: One year prospective cohort with 122 patients separated in group 1, not using HT, group 2 starting the use of HT, and group 3 with prior use of implants of estradiol and testosterone. All patients performed serum dosages of total cholesterol, HDL and triglycerides, in the beginning of the study and after 1 year. DISCUSSION: The use of E and T implants showed some statistically significant decrease in TC at the beginning of the HT and some decrease in LDL in the group using HT. In the group without HT there was no difference in lipid profile.

Hormonal therapy with estradiol and testosterone implants: bone protection?

OBJECTIVE: To assess bone mineral density (BMD) in postmenopausal women using estradiol and testosterone hormonal implants comparing to that of patients without hormonal therapy. DESIGN OF THE STUDY: Sixty-one patients were followed in prospective cohort study separated in Group 1, 34 women using implants and Group 2, 27 women without implants and BMD assessment through Dual energy X-ray absorptiometry was conducted in the beginning of follow-up and after 1 year. RESULTS: The average lumbar spine BMD in Group 1 was 1.123 ± 0.16 kg/m(2) and 1.144 ± 0.18 kg/m(2) after 1 year, p=0.39 and femur BMD was 0.922 ± 0.16 kg/m(2) and 0.957 ± 0.12 kg/m(2) after 1 year of treatment, p=0.076. In Group 2, the initial lumbar spine BMD average was 1.064 ± 0.2 kg/m(2) and after 1 year, 1.001 ± 0.23 kg/m(2), p=0.112 and femur BMD changed from 0.928 ± 0.14 kg/m(2) to 0.881 ± 0.15 kg/m(2) after 1 year, p=0.046. CONCLUSION: BMD variance between the groups in the period of 1 year showed that the combination of estradiol and testosterone promoted bone protection in post menopausal women.

A internação psiquiátrica involuntária e a Lei 10.216/01. Reflexões acerca da garantia de proteção aos direitos da pessoa com transtorno mental / The involuntary psychiatric internment and Law 10.216/01. Reflections concerning the guarantee of protection to the rights of the person with mental upheaval

A dissertação tem como objetivo estudar o aspecto da proteção e dos direitos das pessoas com transtorno mental internadas involuntariamente de acordo com o que determina a Lei 10.216 de 6 de abril de 2001. A aprovação desta lei foi conseqüência de um longo processo de reivindicação e mobilização social proporcionados pelo movimento de Reforma Psiquiátrica. Este trouxe mudanças nas formas de tratar e lidar com a pessoa com transtorno mental, passando a questionar a internação como forma privilegiada de tratamento e estimulando a utilização de redes de serviços de atenção psicossocial. A lei atual, ao conceituar a Internação Psiquiátrica Involuntária (IPI), colocou em cena um novo ator no contexto da psiquiatria, o Ministério Público Estadual, que passou a ter uma função prevista e regulamentada quanto a sua participação no controle e acompanhamento das internações. Por outro lado, os serviços psiquiátricos que realizam este procedimento adquiriram novas responsabilidades ao autorizarem e/ou executarem internações involuntárias. Para a concretização da pesquisa houve o estudo das principais leis brasileiras acerca da saúde mental – Decreto 1.132 de 1903, Decreto 24.559 de 1934 e Lei 10.216 de 2001 – e a realização de um trabalho de campo composto por observação participante e entrevistas envolvendo uma emergência psiquiátrica do município do Rio de Janeiro e o Ministério Público Estadual. Procuramos, através deste trabalho, verificar a atuação dos mesmos no controle e acompanhamento da IPI no que diz respeito à organização do cumprimento dos termos estabelecidos pela legislação, de modo a proporcionar a garantia e a proteção dos direitos da pessoa, fazendo com que essa função tenha efeitos positivos nos serviços de internação e na vida das mesmas.